Roles of Myotubularin PI 3-phosphatases in Demyelinating Peripheral Neuropathy

候选人，弗雷德·罗宾逊博士，过去四年一直在杰克·迪克森博士的实验室接受培训。Dixon博士的实验室位于加州大学圣地亚哥分校（UCSD）医学院药学系。加州大学圣地亚哥分校是一所著名的研究机构，在神经科学、信号转导和癌症生物学领域尤为强大。Dixon博士是蛋白质和脂质磷酸酶研究领域的世界领导者。候选人已经建立了一个新兴的研究项目，专注于了解肌管蛋白家族磷酸肌苷（PI） 3-磷酸酶的突变如何导致Charcot-Marie-Tooth （CMT）周围神经病变。CMT是最常见的遗传性神经系统疾病，2000年美国约有1例CMT患者。CMT导致四肢肌肉进行性退化和感觉功能丧失。4B型CMT （CMT4B）是一种严重的外周神经髓鞘异常的疾病。肌小管蛋白相关蛋白2 （MTMR2）或MTMR13基因的突变都会导致CMT4B。该候选人最近证明MTMR2和MTMR13 PI 3-磷酸酶形成一种膜相关复合物，能够调节3-磷酸肌苷。由于MTMR2或MTMR13的缺失足以引起CMT4B，因此MTMR13可能是MTMR2的重要调节因子。为了进一步探索MTMR2和MTMR13之间的关系，候选人产生了mtmr3缺陷小鼠。该提案的具体目的是(1)验证mtmr3缺陷小鼠作为CMT4B疾病的模型，(2)检查mtmr3缺失对Mtmr2功能的影响，以及(3)确定在mtmr3缺陷的雪旺细胞中，3-磷酸肌苷稳态和内体溶酶体运输是如何被扰乱的。了解雪旺细胞内体-溶酶体途径如何被3-磷酸肌苷的失调所改变，可能使我们考虑将该途径的药理调节作为一种治疗策略。

The Candidate, Dr. Fred Robinson, has been training for the last four years as a fellow in the laboratory of Dr. Jack Dixon. Dr. Dixon's Laboratory is in the Department of Pharmacology at the University of California San Diego (UCSD) School of Medicine. UCSD is a renowned research institution, particularly strong in the fields of neuroscience, signal transduction and cancer biology. Dr. Dixon is a world leader in the study of protein and lipid phosphatases. The Candidate has established a fledgling research program focused on understanding how mutations in myotubularin family phosphoinositide (PI) 3-phosphatases lead to Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT is the most common inherited neurological disorder, affecting about 1 in 2000 in the United States. CMT causes progressive degeneration of the muscles of the extremities and loss of sensory function. Type 4B CMT (CMT4B) is a severe form of the disease in which the myelin sheaths of peripheral nerves are abnormal. Mutations in the genes for either myotubularin related protein 2 (MTMR2) or MTMR13 cause CMT4B. The Candidate recently demonstrated that the MTMR2 and MTMR13 PI 3-phosphatases form a membrane-associated complex capable of regulating 3-phosphoinositides. As loss of either MTMR2 or MTMR13 is sufficient to cause CMT4B, MTMR13 is likely an essential regulator of MTMR2. To further probe the relationship between MTMR2 and MTMR13, the Candidate has generated Mtmrl 3-deficient mice. The specific aims of the proposal are (1) Validate Mtmrl 3-deficient mice as a model of CMT4B disease, (2) Examine the impact of loss of Mtmrl 3 on Mtmr2 function, and (3) Determine how 3-phosphoinositide homeostasis and endosomal-lysosomal trafficking are perturbed in Mtmrl 3-deficient Schwann cells. Understanding how the Schwann cell endosomal-lysosomal pathway is altered by the dysregulation of 3- phosphoinositides may allow us to consider pharmacological modulation of the pathway as a therapeutic strategy. The initial phase of the work (1-2 years) will be carried under Dr. Dixon's supervision. The Candidate will also be mentored by Dr. Katerina Akassoglou, an expert in peripheral nerve biology and demyelination. This phase will focus on characterization of Mtmrl 3-deficient mice and on other aspects of the project for which key training is available at UCSD. Later, as an independent investigator, the Candidate will continue studying Mtmrl 3-deficient mice, focusing more specifically on Schwann cell biology.